SARS-CoV-2 mouse adaptation selects virulence mutations that cause TNF-driven age-dependent severe disease with human correlates

Stefanie M. Bader, James P. Cooney, Dylan Sheerin, George Taiaroa, Leigh Harty, Kathryn C. Davidson, Liana Mackiewicz, Merle Dayton, Stephen Wilcox, Lachlan Whitehead, Kelly L. Rogers, Smitha Rose Georgy, Anna K. Coussens, Samantha L. Grimley, Vincent Corbin, Miranda Pitt, Lachlan Coin, Raelene Pickering, Merlin Thomas, Cody C. AllisonJulie McAuley, Damian F.J. Purcell, Marcel Doerflinger, Marc Pellegrini

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

The diversity of COVID-19 disease in otherwise healthy people, from seemingly asymptomatic infection to severe life-threatening disease, is not clearly understood. We passaged a naturally occurring near-ancestral SARS-CoV-2 variant, capable of infecting wild-type mice, and identified viral genomic mutations coinciding with the acquisition of severe disease in young adult mice and lethality in aged animals. Transcriptomic analysis of lung tissues from mice with severe disease elucidated a host antiviral response dominated mainly by interferon and IL-6 pathway activation in young mice, while in aged animals, a fatal outcome was dominated by TNF and TGF-β signaling. Congruent with our pathway analysis, we showed that young TNF-deficient mice had mild disease compared to controls and aged TNF-deficient animals were more likely to survive infection. Emerging clinical correlates of disease are consistent with our preclinical studies, and our model may provide value in defining aberrant host responses that are causative of severe COVID-19.

Original languageEnglish
Article numbere2301689120
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number32
DOIs
Publication statusPublished - 8 Aug 2023

Keywords

  • COVID-19
  • cytokines
  • inflammation
  • mouse adapted
  • SARS-CoV-2

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